Adolescent epigenetic profiles and environmental exposures from early life through peri-adolescence

Abstract

Epigenetic perturbations induced by environmental exposures at susceptible lifestages contribute to disease development. Even so, the influence of early life and ongoing exposures on the adolescent epigenome is rarely examined. We examined the association of exposure biomarkers for lead (Pb), bisphenol A (BPA), and nine phthalates metabolites with blood leukocyte DNA methylation at LINE-1 repetitive elements and environmentally responsive genes ( IGF2 , H19 , and HSD11B2 ) in peri-adolescents. Participants ( n = 247) from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were followed-up once between the ages of 8 and 14 years, and concurrent exposures were measured in biospecimen collected at that time (blood Pb, urinary BPA, and phthalate metabolites). Prenatal and childhood exposures to Pb were previously approximated using maternal and child samples. BPA and phthalate metabolites were measured in third trimester maternal urine samples. Significant associations ( P < 0.05) were observed between DNA methylation and exposure biomarkers that were gene and biomarker specific. For example, Pb was only associated with LINE-1 hypomethylation during pregnancy ( P = 0.04), while early childhood Pb was instead associated with H19 hypermethylation ( P = 0.04). Concurrent urinary mono (2-ethylhexyl) phthalate (MEHP) was associated with HSD11B2 hypermethylation ( P = 0.005). Sex-specific associations, particularly among males, were also observed. In addition to single exposure models, principal component analysis was employed to examine exposure mixtures. This method largely corroborated the findings of the single exposure models. This study along with others in the field suggests that environment-epigenetic relationships vary by chemical, exposure timing, and sex.

Keywords: DNA methylation; bisphenol A; childhood exposures; lead; phthalates; prenatal exposures.

Figure 1:

exposures at multiple developmental stages throughout early life and DNA methylation in peri-adolescents. To examine the impact of both early life and concurrent EDC exposures on the epigenome, DNA methylation was quantified at LINE-1 and three environmentally-responsive genes ( H19 , IGF2 , and HSD11B2 ) in blood leukocyte DNA from 8- to 14-year-old children of the ELEMENT study. The windows of exposure to Pb, BPA, and phthalates estimated by maternal (during gestation) or child (birth and after) biomarkers are depicted. Abbreviations used in figure: Phth = phthalates (9 metabolites), Tri = trimester, DNA _m =  DNA methylation.

Figure 2:

associations between peri-adolescent H19 methylation and exposure biomarkers from multiple developmental stages. All estimates are from repeated measures models for H19 methylation at 4 CpG sites (from blood leukocyte DNA, PA study visit). Models adjust for children’s age and sex. All estimates give the change in % DNA methylation for an IQR range increase in the exposure biomarker (based on ln-transformed values for all biomarkers except tibia and patella Pb). *Denotes significant associations at the P  ≤ 0.05 level. T3 = Trimester 3 (maternal samples).

Figure 3:

associations between peri-adolescent HSD11B2 methylation and exposure biomarkers from multiple developmental stages. All estimates are from repeated measures models for HSD11B2 methylation at 4 CpG sites (from blood leukocyte DNA, PA study visit). Models adjust for children’s age and sex. All estimates give the change in % DNA methylation for an IQR range increase in the exposure biomarker (based on ln-transformed values for all biomarkers except for tibia and patella Pb). *Denotes significant association at the P  < 0.05 level. T3= trimester 3 (maternal samples).

Figure 4:

Associations between tertiles of BPA exposure and peri-adolescent DNA methylation at four regions. BPA was measured in maternal urine samples from trimester 3 (T3) and children’s urine samples at the PA study visit. All estimates are from repeated measures models of methylation at LINE-1, H19 , HSD11B2 , and IGF2 (at least 4 CpG sites for each). Models adjust for children’s age and sex. Estimates are interpreted as the change in % DNA methylation for tertile 2 or 3 compared with the lowest tertile. *Denotes significant associations at the P  ≤ 0.05 level.